Cytolytic T lymphocytes (CTLs) derived from a cancer patient will often recognize antigens specific to tumor cells. Van der Bruggen P. et al. (1991, Science 254: 1643-1647) identified a gene that directs the expression of one such antigen, MZ2-E, in a human melanoma cell line. This gene, known as MAGE-1, is expressed by other melanoma cell lines and several other types of tumor cells, but is not expressed in a panel of normal tissues. Eleven additional members of a multigene MAGE family, map to the q28 region of chromosome X and have between 64% and 85% identity in amino acid sequence to MAGE-1 (Chen Y. T. et al. (1994) Proc. Natl. Acad. Sci. 91: 1004-1008); De Plaen E. et al. (1994) Immunogenetics 40: 360-369; Wang M. G. et al. (1994) Cytogenet. Cell Genet. 67: 116-119). Six genes of the MAGE family were found to be expressed at a high level in a number of tumors of various histologic types. Examination of a large panel of healthy tissues revealed expression only in testis and placenta (De Plaen E. el al., supra). These initial reports were confirmed with additional studies which found various MAGE genes preferentially expressed in a substantial proportion of colorectal, lung, ovarian, and skin cancers (Mori M. et al. (1996) Ann. Surg. 183-188; Sakata M. (1996) Kurume Med. J. 43: 55-61; Yamada a. et al. (1995) Int. J. Cancer 64: 388-393; Zukut R. et al. (1993) Cancer Res. 53: 5-8). Activation of MAGE-1 in cancer cells may be due to demethylation of the promoter sequence. Treatment with the demethylating agent 5-aza-2'-deoxycytidine activated MAGE-1 expression not only in tumor cell lines, but also in primary fibroblasts (De Smet C. et al. (1996) Proc. Natl. Acad. Sci. 93: 7149-7153).
The MAGE proteins lack signal sequences, but have a small potential transmembrane domain which may associate with the transmembrane domain of another protein (De Plaen E. et al, supra). This region shows a particularly high degree of conservation with the mouse protein necdin, which overall has 31% identity with MAGE-10. Necdin is a nuclear protein, first identified in neuronally differentiated embryonal carcinoma cells and in the brain of adult mice (Maruyama K. et al. (1991) Biochem. Biophys. Res. Commun. 178: 291-296). Uetsuki T. et al. have found that necdin is expressed in virtually all postmitotic neurons in the central nervous system at all stages of development (1996, J. Biol. Chem. 271: 918-924). However, necdin is not expressed in proliferative neuron-like cells originating from tumors and ectopic expression of necdin in NIH3T3 cells suppresscs cell growth without affecting cell viability (Aizawa T. et al., (1992) Dev. Brain Res. 63: 265-274); Hayashi Y. et al., (1995) Biochem. Biophys. Res. Commun. 213: 317-324). Therefore, necdin is likely to act in the transition in developing neurons from proliferative to non-proliferative states (Uetsuki T. et al., supra).
The identification of tumor specific antigens and corresponding T cell epitopes have provided novel peptide-based vaccines useful in treating cancer patients. For example, a nonapeptide fragment of MAGE-1 stimulates CTLs that respond to antigen MZ2-E (Traversari C. et al. (1992) J. Exp. Med. 176: 1453-1457). Cells that present the nonapeptide, EADPT-GHSY, were used to immunize MAGE-1 positive melanoma patients (Hu X. et al. (1996) Cancer Res. 56: 2479-2483). The immunization increased the frequency of autologous melanoma-reactive CTL precursors in the circulation. In combination with interleukin-2 the MAGE-1 nonapeptide immunization led to a significant expansion of the peptide-specific and autologous melanoma-reactive CTL response (Hu et al., supra).
The discovery of polynucleotides encoding MAGE-like proteins, and the molecules themselves, provides a means to investigate cancer and neurodegenerative conditions. Discovery of molecules related to MAGE proteins satisfies a need in the art by providing new compositions useful in diagnosis or treatment of cancer and neurodegenerative conditions.